Muscle glucose uptake (MGU) requires delivery of glucose to muscle, glucose transport into muscle, and glucose phosphorylation in muscle. Control of MGU is distributed between these three steps and insulin resistance is due to a defect in one or more of them. The experiments described herein will characterize the redistribution of MGU control that occurs in response to defined monogenic insulin resistance (endothelial nitric oxide synthase, GLUT4, hexokinase II knockouts) and dietary insulin resistance. The effectiveness of site-specific compensation for these etiologically different forms of insulin resistance will be tested within the broader boundaries of distributed MGU control. Insulin clamps and exercise will be used to amplify, identify, and isolate defects in control of MGU. The means by which acute and chronic exercise decrease functional limitations to MGU, thereby increasing insulin action, will be defined in healthy and insulin resistant states. Experiments will be performed in chronically catheterized, conscious mice. The approach used allows for comprehensive metabolic assessment in vivo in the absence of stress. Control of MGU will be measured using [2-(3H)] deoxyglucose in combination with methods for sampling blood and tissues and measuring muscle blood flow. The relationship of MGU control to long chain fatty acid (LCFA) uptake will be measured isotopically. The specific aims of the proposed studies are to determine in the whole organism, 1) whether monogenic insulin resistances are characterized by the same diffuse redistribution of site-specific MGU control as dietary and LCFA-induced insulin resistance; 2) whether site-specific compensatory mechanisms for monogenic and dietary insulin resistance are effective; 3) the mechanisms which explain the insulin-sensitizing effects of acute and chronic exercise; and 4) whether dysregulation of MGU in insulin resistance is associated with enhanced LCFA uptake and whether compensation for dysregulation of MGU normalizes it. The results from these studies will lead to a greater understanding of the dysregulation of MGU that occurs with insulin resistance and identification of potential treatment strategies.